Stemness and hybrid epithelial-mesenchymal profiles guide peritoneal dissemination of malignant mesothelioma and pseudomyxoma peritonei.

Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial-mesenchymal (E/M) axis. To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity-related genes to measure E/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan-Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1bright-cells identified high-grade PMP, and discriminated solid masses from ascitic/mucin-embedded tumor cells in both forms of PM. Epithelial/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (p = .0343 and p = .0339, respectively, log-rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data.

Is Systemic Chemotherapy Useful in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Peritoneal Metastases? A Propensity-Score Analysis.

PURPOSE: Multimodal treatment of colorectal (CRC) peritoneal metastases (PM) includes systemic chemotherapy (SC) and surgical cytoreduction (CRS), eventually with hyperthermic intraperitoneal chemotherapy (HIPEC), in select patients. Considering lack of clear guidelines, this study was designed to analyze the role of chemotherapy and its timing in patients treated with CRS-HIPEC. METHODS: Data from 13 Italian centers with PM expertise were collected by a collaborative group of the Italian Society of Surgical Oncology (SICO). Clinicopathological variables, SC use, and timing of administration were correlated with overall survival (OS), disease-free survival (DFS), and local (peritoneal) DFS (LDFS) after propensity-score (PS) weighting to reduce confounding factors. RESULTS: A total of 367 patients treated with CRS-HIPEC were included in the propensity-score weighting. Of the total patients, 19.9% did not receive chemotherapy within 6 months of surgery, 32.4% received chemotherapy before surgery (pregroup), 28.9% after (post), and 18.8% received both pre- and post-CRS-HIPEC treatment (peri). SC was preferentially administered to younger (p = 0.02) and node-positive (p = 0.010) patients. Preoperative SC is associated with increased rate of major complications (26.9 vs. 11.3%, p = 0.0009). After PS weighting, there were no differences in OS, DFS, or LDFS (p = 0.56, 0.50, and 0.17) between chemotherapy-treated and untreated patients. Considering SC timing, the post CRS-HIPEC group had a longer DFS and LDFS than the pre-group (median DFS 15.4 vs. 9.8 m, p = 0.003; median LDFS 26.3 vs. 15.8 m, p = 0.026). CONCLUSIONS: In patients with CRC-PM treated with CRS-HIPEC, systemic chemotherapy was not associated with overall survival benefit. The adjuvant schedule was related to prolonged disease-free intervals. Additional, randomized studies are required to clarify the role and timing of systemic chemotherapy in this patient subset.

Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS. METHODS: Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS). RESULTS: The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS. CONCLUSION: For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

Complete pathological response of colorectal peritoneal metastases in Lynch syndrome after immunotherapy case report: is a paradigm shift in cytoreductive surgery needed?

BACKGROUND: We report the first case of a patient affected by peritoneal metastases from colon cancer, arising in the context of Lynch syndrome with pathological complete response. The patient was treated with immunotherapy and cytoreductive surgery. This paper discusses the implications of these novel therapies for the management of PM. CASE PRESENTATION: A 50-year-old man affected by Lynch syndrome was referred to our institution for metachronous peritoneal recurrence of ascending colon adenocarcinoma. As a second-line treatment, he received Nivolumab therapy with stable disease. Patient underwent cytoreductive surgery with residual disease and a pathological complete response. Flow cytometry described a particular immune sub-population response. There was no evidence of disease progression after nine months. CONCLUSION: This is the first report of a Lynch patient affected by peritoneal metastases of colorectal cancer, treated with cytoreductive surgery (CRS) and resulting in a pathological complete response after immune checkpoint inhibitors treatment (ICIs). This case report may suggest that patients with peculiar immunological features could benefit from a tailored approach, since "classical" CRS paradigms may not effectively predict the clinical outcome. Further large-scale studies are needed to determine the correct operative management of such patients (tailored or "standard" CRS), defining the correct surgical timing and eventual discontinuation of ICI therapy after surgery.

The surgical treatment of non-metastatic melanoma in a Clinical National Melanoma Registry Study Group (CNMR): a retrospective cohort quality improvement study to reduce the morbidity rates.

BACKGROUND: Reproducible, high-quality surgery is a key point in the management of cancer patients. Quality indicators for surgical treatment of melanoma has been presented with benchmarks but data on morbidity are still limited. This study presents the quality indicators on morbidity after surgical treatment for non-metastatic skin melanoma in an Italian registry. METHODS: Data were extracted from the Central National Melanoma Registry (CNMR) promoted by the Italian Melanoma Intergroup (IMI). All surgical procedures (WE, SNLB or LFND) for non-metastatic skin melanoma between January 2011 and February 2017 were evaluated for inclusion in the study. Only centers with adequate completeness of information (> 80%) were included in the study. Short-term complications (wound infection, dehiscence, skin graft failure and seroma) were investigated. RESULTS: Wound infection rate was 1.1% (0.4 to 2.7%) in WE, 1.3% (0.7 to 2.5%) in SLNB and 4.1% (2.1 to 8.0%) in LFND. Wound dehiscence rate was 2.0% (0.8 to 5.1%) in WE, 0.9% (0.2 to 3.0%) in SLNB and 2.8% (0.9 to 8.6%) in LFND. Seroma rate was 4.2% (1.5 to 11.1%) in SLNB and 15.1% (4.6 to 39.9%) in LFND. Unreliable information was found on skin graft failure. CONCLUSIONS: Our findings contribute to available literature in setting up the recommended standards for melanoma centers, thus improving the quality of surgery offered to patients. A consensus on the core issues around surgical morbidity is needed to provide practical guidance on morbidity prevention and management.

Complete mesocolic excision versus conventional hemicolectomy in patients with right colon cancer: a systematic review and meta-analysis.

PURPOSE: Complete mesocolic excision (CME) has introduced a promising surgical approach for treatment of right colon cancer. However, benefits of CME are still a matter of debate. We conducted a systematic review and meta-analysis to assess safety and long-term outcomes of CME versus conventional right hemicolectomy (CRH). METHODS: We systematically searched MEDLINE, the Cochrane Database of Systematic Reviews, Scopus, Web of Science, and Embase for retrieving studies comparing CME with CRH in right colon cancer. After data extraction from the included studies, meta-analysis was performed to compare postoperative complications, anastomotic leakage, 30-day mortality, number of lymph node yield, disease-free survival (DFS), and overall survival (OS). RESULTS: Eight studies met the inclusion criteria with a total of 1871 patients enrolled. No difference was observed in postoperative complications (OR 1.13, 95% CI 0.88-1.47, p = 0.34). CME was associated with significantly higher number of lymph nodes retrieved (MD 9.17, CI 4.67-13.68, p < 0.001). CME also improved 3-year OS (OR 1.57, 95% CI 1.17-2.11, p = 0.003), 5-year OS (OR 1.41, 95% CI 1.06-1.89, p = 0.02), and 5-year DFS (OR 1.99, 95% CI 1.29-3.07, p = 0.002). A sub-group analysis for patients with stage III colon cancer showed no significant impact of CME on 3-year and 5-year OS (OR 2.47, 95% CI 0.86-7.06, p = 0.09; OR 1.23, 95% CI 0.78-1.94, p = 0.38). CONCLUSION: Although with limited evidence, CME shows similar postoperative complication rates and an improved survival outcome compared with CRH.

Oncological outcome of videoscopic groin dissection for lymph node metastasis from melanoma.

BACKGROUND: Videoscopic inguinal lymphadenectomy (VIL) represents an innovative approach for patients with melanoma lymph node (LN) metastases, mainly aimed at lowering wound-related morbidity. However, long-term data on oncologic safety are still lacking. The aim of this study is to review the oncologic outcome of videoscopic groin dissection in a single institution caseload. METHODS: Data were prospectively gathered on patients with inguinal melanoma metastasis who underwent VIL. Clinical data included age, race, sex, tumor histology, node counts and number of metastatic nodes. Disease-free survival and overall survival were monitored based on an institutional follow-up schedule. The study was approved by the local ethics committee (Video-SIIO II study). RESULTS: We analyzed 48 videoscopic groin dissections performed in 50 patients (2 patients underwent bilateral VIL). Median age was 54.5 years. Female/male ratio was 15/33. Indication for surgery was positive inguinal sentinel biopsy and cytological confirmed clinical disease in 40 and 10 cases, respectively. Median LN retrieval count was 19. After a median follow-up of 28 months, groin recurrence (lymphatic basin) was observed in one single case. CONCLUSIONS: VIL for melanoma LN metastases is associated with a favorable oncologic outcome. In particular, LN yield and locoregional recurrence rate obtained with videoscopic dissection are comparable to those reported with the open technique. Prospective studies are needed to confirm these results in a larger cohort of patients.

Role of Epithelial-Mesenchymal Plasticity in Pseudomyxoma Peritonei: Implications for Locoregional Treatments.

The mechanisms by which neoplastic cells disseminate from the primary tumor to metastatic sites, so-called metastatic organotropism, remain poorly understood. Epithelial-mesenchymal transition (EMT) plays a role in cancer development and progression by converting static epithelial cells into the migratory and microenvironment-interacting mesenchymal cells, and by the modulation of chemoresistance and stemness of tumor cells. Several findings highlight that pathways involved in EMT and its reverse process (mesenchymal-epithelial transition, MET), now collectively called epithelial-mesenchymal plasticity (EMP), play a role in peritoneal metastases. So far, the relevance of factors linked to EMP in a unique peritoneal malignancy such as pseudomyxoma peritonei (PMP) has not been fully elucidated. In this review, we focus on the role of epithelial-mesenchymal dynamics in the metastatic process involving mucinous neoplastic dissemination in the peritoneum. In particular, we discuss the role of expression profiles and phenotypic transitions found in PMP in light of the recent concept of EMP. A better understanding of EMP-associated mechanisms driving peritoneal metastasis will help to provide a more targeted approach for PMP patients selected for locoregional interventions involving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Novel Therapy for Pediatric Angiosarcoma With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

The management of pediatric abdominopelvic angiosarcoma remains unclear due to limited clinical experience. Herein, we presented the first 2 pediatric patients with abdominal angiosarcoma who were treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) after neoadjuvant therapy. The first patient is alive with recurrent disease at 1-year follow-up and the second patient remains disease free after 1 year. CRS and HIPEC should be considered as a therapeutic option in the management of pediatric abdominal angiosarcomas. A multi-institutional international shared registry is needed to further evaluate the role of CRS and HIPEC in inducing remission of abdominopelvic angiosarcomas in the pediatric population.

Multiple Lymph Node Basin Drainage in Trunk Melanoma Is Not Associated with Survival of Sentinel Lymph Node-Positive Patients.

OBJECTIVES: This study was aimed at investigating the prognostic role of multiple lymph node basin drainage (MLBD) in patients with positive sentinel lymph node (SLN) biopsy. BACKGROUND: MLBD is frequently observed in patients with trunk melanoma undergoing SLN. The prognostic value of MLBD in SLN-positive patients is still debated. METHODS: Retrospective data from 312 trunk melanoma patients with positive SLN biopsy (1991-2012) at 6 Italian referral centres were gathered in a multicentre database. MLBD was defined at preoperative lymphoscintigraphy. Clinical and pathological data were analysed for their association with disease-free interval (DFI) and disease-specific (DSS) survival. RESULTS: MLBD was identified in 34.6% of patients (108/312) and was significantly associated with >1 positive SLN (37 vs. 15.2%; p < 0.001) and with >1 positive lymph node (LN) after complete lymph node dissection (CLND) (50.9 vs. 34.8%; p = 0.033). No differences were observed according to drainage pattern in patients who had negative and positive non-SLN at CLND. MLBD was not associated with either DFI or DSS. Multivariate analyses showed that tumour thickness, ulceration, and number of metastatic LNs were associated with worse DFI and DSS, while regression confirmed its protective role in survival. CONCLUSION: In positive SLN patients, MLBD has no association with survival, which is mainly related to American Joint Committee on Cancer (AJCC) prognostic factors. Since the overall number of positive LNs drives the prognosis, the importance of a CLND in all the positive basins is confirmed.

Laparoscopic splenectomy for sclerosing angiomatoid nodular transformation of the spleen.

Sclerosing angiomatoid nodular transformation (SANT) is a rare, benign, proliferative vascular lesion that arises from the splenic red pulp. Most patients with SANT have no clinical symptoms and are discovered incidentally on imaging. There are no definitive radiological signs and a distinction from other splenic diseases, and malignant processes remain difficult. Confirmation of the diagnosis of SANT requires a histological and immunohistochemical evaluation of the resected spleen. Here, we report an unusual case of SANT of the spleen successfully treated with an elective laparoscopic splenectomy (LS). LS is a safe and effective method for diagnosis of SANT.

Prognostic Role of Multiple Lymphatic Basin Drainage in Sentinel Lymph Node-Negative Trunk Melanoma Patients: A Multicenter Study from the Italian Melanoma Intergroup.

BACKGROUND: Multiple lymphatic basin drainage (MLBD) is frequently observed in patients with trunk melanoma undergoing sentinel lymph node (SLN) biopsy. Conflicting data regarding the prognostic association of MLBD in SLN-negative patients have been reported. This study aimed to investigate the prognostic role of MLBD in patients with negative SLN biopsy. METHODS: Retrospective data from 656 melanoma patients who underwent a SLN biopsy (1991-2012) at six Italian centers were gathered in a multicenter database. MLBD was defined as lymphoscintigraphic and intraoperative identification of an SLN in more than one nodal basin. Clinical and pathologic variables were recorded and analyzed for their impact on survival. RESULTS: SLN-negative patients with MLBD were at lower risk of melanoma recurrence [hazard ratio (HR) 0.73, P = 0.05) and melanoma-related death (HR 0.68, P = 0.001) independent of common staging features. Multivariable Cox analyses of disease-free interval (DFI) and disease-specific survival (DSS) showed that MLBD maintained a favorable role and ulceration an unfavorable role. Histologic regression was independently associated only with DFI. When survival was stratified according to presence of MLBD, histologic regression and Breslow thickness <2 mm were associated with improved DFI (5-year DFI: 96.9 vs. 66,1 %, respectively; HR 0.48, P < 0.001) and DSS (5-year DSS: 96.7 vs. 71.8 %, respectively; HR 0.52, P = 0.005) compared to patients without these three favorable parameters. CONCLUSIONS: Patients with negative SLN biopsy results have better prognosis when two or more lymphatic basins are identified and analyzed. Further research is required to investigate the mechanisms behind this evidence.

Laparoscopic Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Metastasis: Improved Short-term Outcomes Revealed Through Propensity Score Matching Analysis.

INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the standard of care for selected cases of primary or secondary peritoneal surface malignancies. The study aims to verify the postoperative advantages of laparoscopic CRS-HIPEC. METHODS: A retrospective analysis of patients who underwent CRS-HIPEC at our institution was performed. Records were extracted from a prospectively maintained database. Patients were divided into two groups, laparoscopic CRS-HIPEC and open CRS-HIPEC, and matched for age, ASA, comorbidities, Prior Surgical Score (PSS), and Peritoneal Cancer Index (PCI) using propensity score analysis. Demographics, clinical, and operative data were compared between the two groups using chi-square or Fisher's exact test and T-test or Mann-Whitney U test. RESULTS: Between 2016 and 2022, 13 patients underwent laparoscopic CRS-HIPEC. These were matched to 32 open CRS-HIPEC patients (1:2.5), obtaining comparable demographics and clinical and preoperative variables. The two groups had a similar duration and complexity of surgery; however, the mean estimated blood loss was lower during laparoscopic procedures (p = 0.008). Overall morbidity rates were lower after laparoscopic CRS-HIPEC (p = 0.043); however, grade III-IV complications, reintervention, and 90-day readmission rates were comparable between the two groups. A faster postoperative recovery in all aspects of the postoperative course was observed, including hospital length of stay (6 vs. 9.5 days, p = 0.003). CONCLUSIONS: Laparoscopic CRS-HIPEC is a feasible and safe procedure and shows improved short-term postoperative outcomes in selected patients with limited peritoneal disease compared to the open approach.

Doxorubicin as Risk Factor for Fascial Dehiscence After CRS-HIPEC for Peritoneal Metastases.

BACKGROUND/AIM: Among postoperative complications, fascial dehiscence (FD) is registered in up to 10% of patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). This study aimed to evaluate the risk factors related to FD after CRS-HIPEC. PATIENTS AND METHODS: A retrospective analysis of a prospectively maintained database of consecutive patients who underwent CRS-HIPEC between 2015 and 2023 was performed. For each patient, risk factors for postoperative fascial dehiscence were identified using multivariate analysis. RESULTS: During the study period (2018-2023), 217 patients were treated with CRS-HIPEC. The incidence of FD was observed in seven cases (3.2%), which were reoperated with direct fascial closure. In three cases, FD was associated with other grade III-IV complications. Body mass index, (BMI; p=0.024), doxorubicin-based HIPEC (p=0.005), and open technique (p=0.004) were identified as risk factors for FD in univariate analysis. Systemic chemotherapy, prior surgical score, and peritoneal cancer index (PCI) were not associated with an increased risk of FD. In multivariable regression analysis, doxorubicin-based HIPEC and open technique were confirmed as risk factors for FD. CONCLUSION: Although FD is a relatively rare event after CRS-HIPEC, open technique and doxorubicin-based HIPEC were significant predictors of this complication. Specific fascial closure techniques and proper wound care should be considered in high-risk patients.

Systemic Chemotherapy in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery: Systematic Review and Meta-Analysis.

BACKGROUND: For patients with colorectal cancer (CRC) peritoneal metastases (PM) who are eligible for cytoreductive surgery (CRS), the indication and timing of systemic chemotherapy (SC) are still under debate. This study aims to analyze the role of pre, post or perioperative SC on the survival and surgical complications of patients treated with CRS-HIPEC. METHODS: After a systematic search in MEDLINE, Cochrane Database of Systematic Reviews, Scopus, Web of Science and Embase, a meta-analysis was performed to compare postoperative complications, disease-free survival (DFS) and overall survival (OS) according to SC administration and timing. PROSPERO: CRD42023478977. RESULTS: Of 1203 studies screened, 15 were included in the meta-analysis (4523 patients). Post-operative SC was associated with increased overall survival (post-SC vs. no post-SC: HR 0.81, p = 0.00001, I2 = 0%; pre-SC vs. post-SC: HR 0.65, p = 0.01, I2 = 28%), whereas SC (pre or post) or pre-SC compared to surgery alone was not (SC vs. no SC: p = 0.29, I2 = 80%; pre-SC vs. no pre-SC: p = 0.59, I2 = 58%). Similar results were seen for DFS. SC was not associated with an increased complication rate (p = 0.47, I2 = 64%). CONCLUSIONS: Systemic chemotherapy administration in patients undergoing radical surgery for colorectal peritoneal metastases is associated with increased survival only in the adjuvant/post-operative setting. Considering the limitations of the included studies, further trials are needed to answer this unresolved question.